This invention relates to novel spiro compounds useful as glycoprotein IIb/IIIa antagonists for the prevention of thrombosis.
The most prevalent vascular disease states are related to platelet dependent narrowing of the blood supply such as atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, anastomosis of vascular grafts, and etc. These conditions represent a variety of disorders thought to be initiated by platelet activation on vessel walls.
Platelet adhesion and aggregation is believed to be an important part of thrombus formation. This activity is mediated by a number of platelet adhesive glycoproteins. The binding sites for fibrinogen, fibronectin and other clotting factors have been located on the platelet membrane glycoprotein complex IIb/IIIa. When a platelet is activated by an agonist such as thrombin the GPIIb/IIIa binding site becomes available to fibrinogen, eventually resulting in platelet aggregation and clot formation.
Heretofore it has been proposed to block these thrombus formation sites by the use of various therapeutic agents.
There is a need in the area of cardiovascular and cerebrovascular therapeutics for new agents which can be used in the prevention and treatment of thrombi.
It is a discovery of this invention that certain novel Spiro compounds block the GPIIb/IIIa fibrinogen receptor, thereby inhibiting platelet aggregation and subsequent thrombus formation. Pharmaceutical formulations containing the Spiro compounds of this invention inhibit aggregation and are useful for the prophylaxis and treatment of thrombogenic diseases, such as myocardial infarction, angina, stroke, peripheral arterial disease, disseminated intravascular coagulation and venous thrombosis.
The present invention covers novel spiro compounds having a spiro nucleus formed from two fused rings, A and B, represented by the formula (I), as hereinafter defined, and all pharmaceutically-acceptable salts, solvates and prodrug derivatives thereof: 
having substituents and subscripts; Q, xe2x80x94(L)xe2x80x94, Ai, p, R10, m, n, R0, Bj, q, and R3, as hereinafter defined.
Another aspect of the invention is a pharmaceutical formulation containing a novel spiro compound of the invention.
Another aspect of the invention is a method of inhibiting platelet aggregation, inhibiting fibrinogen binding, or preventing thrombosis by administering to a mammal the novel Spiro compounds of the invention.
Another aspect of this invention is a method of treating a human to alleviate the pathological effects of atherosclerosis and arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks and strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis following angioplasty, carotid endarterectomy, and anastomosis of vascular grafts; wherein the method comprises administering to said human a therapeutically-effective amount of a novel spiro compound of this invention.
Definitions:
The term xe2x80x9cspiroxe2x80x9d refers to a compound consisting of two rings having only one carbon atom in common. Spiropentane is an exemplary compound having a Spiro system. Spiro systems exclude other bicyclic compounds such as naphthalene which have two or more carbon atoms in common.
The term xe2x80x9calkylxe2x80x9d used herein refers to a monovalent straight or branched chain radical of from one to ten carbon atoms, including, but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-hexyl, and the like.
The term xe2x80x9chalosubstituted alkylxe2x80x9d as used herein refers to an alkyl group as just defined, substituted by one, two or three halogen atoms selected from fluorine, chlorine, bromine, and iodine. Examples of such groups include chloromethyl, bromoethyl, trifluoromethyl, and the like.
The term xe2x80x9carylxe2x80x9d when used alone means a homocyclic aromatic radical whether or not fused. Preferred aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
The term xe2x80x9csubstituted arylxe2x80x9d denotes an aryl group substituted with one, two, or three substituents chosen from halogen, hydroxy, protected hydroxy, cyano, nitro, C1-C10 alkyl, C1-C10 alkoxy, trifluoromethyl, amino, aminomethyl, and the like. Examples of such groups are 4-chlorophenyl, 2-methylphenyl, 3-methyl-4-hydroxyphenyl, and 3-ethoxyphenyl.
The term xe2x80x9carylalkylxe2x80x9d means one, two or three aryl groups having the number of carbon atoms designated, appended to an alkyl radical having the number of carbon atoms designated. A typical arylalkyl group is the benzyl group.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a monovalent straight or branched chain radical of from two to six carbon atoms containing a carbon double bond including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from one to ten carbon atoms, including but not limited to, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94. xe2x80x94(CH2)3xe2x80x94, xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(C2H5)xe2x80x94, xe2x80x94CH(CH3)CH2xe2x80x94, and the like.
The term xe2x80x9calkenylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon double bond, including but not limited to, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90C(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH(CHxe2x95x90CH2)CH2, and the like.
The term xe2x80x9calkynylenexe2x80x9d as used herein refers to a divalent straight or branched chain group of from two to ten carbon atoms containing a carbon-carbon triple bond, including but not limited to, 
and the like.
The term xe2x80x9camidinoxe2x80x9d refers to the radical having the structural formula; 
The term xe2x80x9cbasic radicalxe2x80x9d refers to an organic radical which is a proton acceptor. Illustrative basic radicals are amino and amidino. Basic radicals may also be formed from a ring nitrogen.
The term xe2x80x9cbasic groupxe2x80x9d refers to an organic group containing one or more basic radicals. A basic group may comprise only an basic radical.
The term xe2x80x9cacid radicalxe2x80x9d refers to an organic radical which is a proton donor. Illustrative acid radicals include; 
The term xe2x80x9cacidic groupxe2x80x9d is an organic group containing one or more acid radicals. An acidic group may comprise only an acid radical.
The term xe2x80x9cnon-interfering substituentxe2x80x9d refers to an organic radical which does not significantly reduce the therapeutic effectiveness of a compound.
Compounds of the Invention:
This invention provides compounds of the general formula (I), or a pharmaceutically-acceptable salt, solvate or or prodrug thereof: 
wherein;
the atoms Ai and Bi are independently selected from carbon, nitrogen, oxygen or sulfur, provided that at least one atom of Ai is carbon, and at least one atom Bj is carbon;
the rings of the spirobicycle formed by Ai and Bj, respectively, may optionally be partly unsaturated;
p and q are independently numbers from 2 to 6;
m is a number from zero to p;
R10 is the same or different and is a non-interfering substituent independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S, with the proviso that only one R10 may be xe2x95x90O or xe2x95x90S, if p is 2 or one or two R10 may be xe2x95x90O or xe2x95x90S, if p is a number from 3 to 6;
n is the number from zero to q;
R0 is the same or different and is a non-interfering substituent independently selected from hydrogen, alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S, with the proviso that only one R0 may be xe2x95x90O or xe2x95x90S, if q is 2 or one or two R0 may be xe2x95x90O or xe2x95x90S, if q is a number from 3 to 6;
the linking group xe2x80x94(L)xe2x80x94 is a bond or a divalent substituted or unsubstituted chain of from 1 to 10 atoms selected from the group consisting of carbon, nitrogen, sulfur, and oxygen;
Q is a basic group containing one or more basic radicals; and
R3 is an acidic group containing one or more acid radicals.
Compounds of the Invention with Preferred Spiro Nuclei:
A compound of formula (II), or a pharmaceutically-acceptable salt, solvate or prodrug thereof:
Q-(L)z-Z-R3xe2x80x83xe2x80x83(II) 
wherein Z is a spirocyclic nucleus selected from (A), (B), (C), or (D) below
wherein:
the group Q-(L)z- is bound to the nitrogen containing ring of nuclei (A), (B), (C), or (D) and the group R3 is bound to the ring formed by the groups A41, A42, A43, A51, A52, A53, A54, A61, A62, A63, A64, A65, A71, A72, A73, A74, A75, or A76; or
the group R3 is bound to the nitrogen containing ring and the group Q-(L)z- is bound to the ring formed by the groups A41, A42, A43, A51, A52, A53, A54, A61, A62, A63, A64, A65, A71, A72, A73, A74, A75, or A76;
r and s are independently a number from zero to 5 with the proviso that not both r or s are 0 and (r+s) is not more than 6, and z is zero or one;
atoms A41, A42, A43, A51, A52, A53, A54, A61, A62, A63, A64, A65, A71, A72, A73, A74, A75, or A76 are independently selected from carbon, nitrogen, oxygen or sulfur, provided that at least one of said atoms is carbon;
the hydrogens of the nitrogen containing part of the spirocycle Z may be substituted by a number of m substituents R10, wherein;
m is a number from zero to (r+s); and
R10 is the same or different and is a non-interfering substituent independently selected from alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S, with the proviso that only one or two R10 may bexe2x95x90O or xe2x95x90S;
n is a number from zero to 3 in Z of having nuclei (A), or a number from zero to 4 in Z having nuclei (B), a number from zero to 5 in Z having nuclei (C), or a number from zero to 6 in Z having nuclei (D);
R0 is the same or different and is a non-interfering substituent independently selected from alkyl, halosubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, hydroxy, alkoxy, arylalkoxy, amino, substituted amino, carbamoyl, carboxy, acyl, cyano, halo, nitro, sulfo, xe2x95x90O, or xe2x95x90S, with the proviso that only one or two R0 may be xe2x95x90O or xe2x95x90S; and
Q, L, and R3 are as defined previously for the formula I compounds.
Representative Spirocyclic Nuclei:
The spirocyclic compounds of the invention include spirocyclic nuclei selected from the group represented by the following structural formulae: 
Representative Oxo Substituted Spirocyclic Nuclei are as Follows:
Oxo substituted spirocyclic compounds of the invention include spirocyclic nuclei selected from the group represented by the following structural formulae: 
Preferred spirocyclic nuclei include the following nuclei: 
where m is one or two.
A group of more preferred spirocyclic nuclei includes the following groups: 
where m is one or two.
A second group of more preferred nuclei include the following: 
where m is one or two.
The most preferred spirocyclic nuclei include teh following nuclei: 
where m is one or two.
The Basic Substituent O:
The substituent Q of formulae (I) and (II) is a basic group. A basic group contains one or more basic radicals. Suitable basic radicals contain one or more nitrogen atoms and include amino, imino, amidino, hydroxyamidino, N-alkylamidines, N,Nxe2x80x2-dialkyamidines, N-arylamidines, aminomethyleneamino, iminomethylamino, guanidino, aminoguanidino, alkylamino, dialkylamino, trialkylamino, alkylideneamino, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, amide, thioamide, benzamidino, pteridinyl, 4aH-carbozolyl, carbozolyl, beta-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, or any of the preceding substituted with amino, imino, amidino, hydroxyamidino, aminomethyleneamino, iminomethylamino, guanidino, alkylamino, dialkylamino, trialkylamino, tetrahydroisoquinoline, dihydrosioindole, alkylideneamino groups or a group represented by the formula; 
Preferred basic radicals are selected from amino, piperidyl, guanidino, hydroxyamidino, and amidino. The most preferred basic radicals are amidino, hydroxyamidino, and piperidyl represented by the formulae; 
The basic group and linker, Q-(L)z-, may have the form of a basic radical pendant on a cyclic ring as shown in formula IV below. The D of Formula (IV) ring may also have substituents R20 which are selected from chlorine, fluorine or non-interfering organic radicals. Fluorine is preferred as a substituent on the D ring. The R20 substituents may be t in number, where t is an integer from zero to the number of unsatisfied bonds in the D ring. The basic radical(s) attaches to the D ring in the manner shown in formula (IV) below: 
Suitable D rings are formed from a nucleus selected from the group consisting of; benzene, cycloheptadiene, cycloheptatriene, cycloheptane, cyclohexane, cyclohexene, cyclohexadiene, cycloheptene, cyclooctadiene, cyclooctane, cyclooctatetraene, cyclooctene, cyclopentane, cyclopentene, imidazole, isooxazole, morpholine, oxazole, piperazine, piperidine, pyrazine, pyrazole, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, tetrahydropyridine, tetrahydropyrimidine, 1H-tetrazole, thiazolidine, thiazole, thiopyran, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole, dihydrofuran, dihydropyran, dioxane, dioxepin, dioxolane, furan, oxocane, tetrahydrofuran, tetrahydropyran, thiophene, and tetrahydrothiophene.
An illustrative species of formula (IV) is the basic radical attached to a benzene ring as shown in formulae (V) and (VI) below: 
The preferred basics groups include the following groups: 
wherein R20 is hydrogen or halogen.
The Acidic Substituent R3 
The substituent R3 of formula (I) or (II) is an acidic group. An acidic group contains one or more acidic radicals. Suitable acidic radicals contain one or more proton donors, and include groups such as sulfonic acids, tetrazoles, phosphonic acids, carboxylic acids, and the like. The acidic radical may be bound to an aryl group, such as phenyl or substittued phenyl, or bound to alkyl chains, such as methylene. These groups may also be bound to the spirocyclic nucleus through alkyl chains having heteroatoms, suchs as S, O, or N, and amide (CONH) or carbonyl (CO) groups. The acidic substituent may also comprise an xcex1-sulfonamido carboxylic acid group of the formula: 
Preferred Spiro Compounds are as Follows:
The formula II spirocyclic compounds, a preferred subset of the formula I spirocyclic compounds, which are preferred compounds of the invention include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivatives, as follows: 
wherein X is F or H, m is zero to four, and n is one to four.
A more preferred subset of the formula I spirocyclic compounds include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivatives, as follows: 
wherein X is F or H, m is zero to four, and n is one to four.
A second preferred subset of the formula I spirocyclic compounds include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivatives, as follows: 
wherein X is F or H.
A second more preferred subset of the formula I spirocyclic compounds include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivatives, as follows: 
wherein X is F or H.
A most preferred subset of the formula I spirocyclic compounds include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivative as follows: 
wherein X is F or H, m is zero to four, and n is one to four.
A second most preferred subset of the formula I spirocyclic compounds include the following compounds, their pharmaceutically-acceptable salts, solvates, and prodrug derivatives, as follows: 
wherein X is F or H.
The compounds of the invention possess at least one acidic functional substituent (viz., R3 of Formula I or II) and, as such, are capable of forming salts. Representative pharmaceutically-acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an anion exchange resin on the salt cycle.
Included within the definition of pharmaceutically-acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine actions, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et. al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66: 1-19 (1977)).
The basic portion of the compounds of the invention (viz., part Q of formula I or II) may be reacted with suitable organic or inorganic acids to form salts of the invention. Representative salts include those selected from the group comprising; acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, chloride, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanllate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate.
The compounds of the formula (I) or (II) can also be in the form of zwitterions, since they contain both acidic and basic functionality and are capable of self-protonation.
Certain compounds of the invention possess one or more chiral centers and may thus exist in optically active forms, or as mixtures of diastereomers. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans-isomeric forms of the compounds. The R- and S-isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans-isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods.
Prodrug Derivatives of Compounds of the Invention:
Prodrugs are derivatives of the compounds of the invention which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. For example, ester derivatives of compounds of this invention are often active in vivo, but not in vitro. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with an amine. Simple aliphatic or aromatic esters derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.
Preferred are the C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention (per formula I or II) Particularly preferred are the C1-C4 alkyl esters, for example, where the R3 acidic group has been esterified to form a group represented by one of the following formulae: 
Acylated basic radicals which are part of basic group on the compounds of the invention have been found to significantly enhance bioavailability. Without being bound by any theory of operation, it is believed that lowering the basicity of basic group (O) makes the compounds of this invention less subject to xe2x80x9cfood effectxe2x80x9d, that is, they have good availability in therapeutic administration to an animal without fasting.
Compounds of this invention may beneficially be dual prodrug derivatives. For example, the acidic group (R3) may be reacted to form an ester and the basic group may additionally be reacted to form an acylated basic derivative. The prodrug derivatives of the compounds of this invention may be combined with other features herein taught to enhance bioavailability, for example, substitution of fluorine atoms on the basic benzamidine group.
Another highly preferred class of prodrugs of the invention are those formed by acylating the basic radicals present on the compounds of the invention. The acyl portion of the acylated basic radical has the general formula: 
where R is C1-C8 alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl; and X is a bond, O, S, or N. Preferably R is C1-C4 alkyl and X is oxygen. For example, acylated basic radical prodrugs of the invention are prepared and illustrated in A, B, C, and D below:
A) acylation of amidine results in a prodrug derivative group: 
B) acylation of a cyclic amine such as piperidine results in a prodrug derivative group: 
C) acylation of guanidine results in a prodrug derivative group: 
D) acylation of a primary amine results in a prodrug derivative group: 
xe2x80x83where, for A, B, C, and D above, R and X are as defined above for the acylated portion of the basic group.
Preparation of Spiro Compounds:
The synthesis of Spiro compounds covered by the invention is described in Scheme 1 thru Scheme 11, in which the following terms are used:
P means a general protective group for amines like benzyl, tert.-butoxycarbonyl, benzyloxycarbonyl, or ethoxycarbonyl.
X, when present, is a spacer typically consisting of a chain of up to three carbon atoms, e.g. methylene, dimethylene, or trimethylene.
Scheme Nomenclature;
The substituent R is a non-interfering substituent illustrated by an alkyl group selected from ethyl, methyl, or tert.-butyl forming esters containing the group COOR, which are cleaved to the corresponding carboxylic acids (Rxe2x95x90H). 
Scheme 1 describes the synthesis of 1-oxa-3,8-diaza-spiro[4.5]decan-2-ones (see J. M. C aroon, R. D. Clark, A. F. Kluge, J. T. Nelson, A. M. Strosberg, St. H. Unger, A. D. Michel, R. L. Whiting, J. Med. Chem. 1981, 24, 1320). 4-Piperidinone is N-protected, e.g. by reaction with benzyl chloroformate, and this compund is converted to the shown epoxide by addition of a methylene group using trimethylsulfoxonium iodide/sodium hydride in DMSO. The ring opening of the epoxide requires heating with an excess of 4-cyanoaniline, and the following formation of the spiro-oxazolidinone is achieved with N,Nxe2x80x2-carbonyl diimidazole, diethyl carbonate, or with phosgene. After removal of the protective group the piperidine is alkylated with an xcfx89-halogenocarboxylate like ethyl bromoacetate or ethyl 4-bromobutanoate. Finally, the nitrile is converted to the amidine by reaction with ethanolic hydrochloric acid followed by treatment with ammonia, and the ethyl ester is cleaved under mild aqueous basic conditions to give the amidino carboxylic acid. 
The synthesis of 3-phenyl-1-oxa-2,8-diaza-spiro[4.5]dec-2-enes is outlined in Scheme 2. 4-Methylene-piperidines like 1-(tertbutoxycarbonyl)-4methylene-piperidine are prepared from the corresponding N-protected piperidinones by Wittig reaction. The five-membered ring is formed by addition of 4-cyanobenzonitrile oxide, which is generated in situ from 4-cyanobenzohydroximinoyl chloride with triethylamine (see K. C. Liu, B. R. Shelton, R. K. Howe, J. Org. Chem. 1980, A, 3916; L. Fisera, F. Sauter, J. Fr{dot over (O)}hlich, Y. Feng, P. Ertl, K. Mereiter, Monatshefte Chem. 1994, 12, 553). The protective group is removed with trifluoroacetic acid followed by alkylation of the spiropiperidine and conversion of the nitrile to the amidine as described in the previous Scheme. 
The synthesis of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane derivatives is described in Scheme 3. N-protected piperidin-4-ones like 1-benzyloxycarbonyl-piperidin-4-one are converted to the corresponding spirohydantoins by heating with a mixture of potassium cyanide and ammonium carbonate (see G. Winters, V. Aresi, G. Nathansohn, Farmaco, Ed. Sci. 1970, 25, 681). The protective group is removed by hydrogenation, and the piperidine is treated with 4-cyanobenzoyl chloride. Alkylation of this intermediate with xcfx89-halogenoalkanoates gives the shown 3-substituted derivatives, and in a second alkylation step the nitrogen at position 1 may be alkylated with alkyl halides Rxe2x80x2Hal, e.g. with benzyl bromide leading to 1-benzyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decanes (see O. O. Orazi, R. A. Corral, H. Schuttenberg, J. Chem. Soc., Perkin Trans. I, 1974, 219). The preferred method for conversion of the benzonitrile to an amidine employs the sequence of addition of hydrogen sulfide, alkylation of the intermediate primary thioamide with methyl iodide, heating with ammonium acetate, and purification of the crude amidine after protection with tert.-butoxycarbonyl. In a final step the protective group is removed with trifluoroacetic acid. If the acidic side chain has been masked by an tert.-butyl ester this one is also cleaved under these conditions. 
In an alternative sequence 1-substituted 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane derivatives may be prepared as shown in Scheme 4 (see G. M. Carrera, Jr., D. S. Garvey, J. Heterocyclic Chem. 1992, 29, 847). The piperidone is treated with a mixture of potassium cyanide and a primary amine like benzyl amine. The intermediate 4-amino-4-cyanopiperidine is hydrolyzed followed by ring closure with potassium cyanate. The following steps including the alkylation of the nitrogen in position 3 with xcfx89-halogenoalkanoates and formation of the amidine is carried out as described in Scheme 4. 
Scheme 5A describes the synthesis of 1,3-dioxo-2,8-diaza-spiro[4.5]decane derivatives (see E. Jucker, R. Sxc3xcexcex2 Arch. Pharm. 1961, 294/66, 210; Helv. Chim. Acta 1977, 4, 1135; Y. Ishihara, H. Yukimasa, M. Miyamoto, G. Goto, Chem. Pharm-Bull. 1992, 40, 1177). The shown 2-cyanoacrylate is formed by Knoevenagel condensation between N-protected piperidin-4-ones like N-benzylpiperidinone and ethyl cyanoacetate. It is heated with potassium cyanide in ethanol/water followed by hydrolysis with hydrochloric acid. The diacid may be purified by reesterification followed by another hydrolysis step of the substituted diethyl succinate, and the succinic acid is converted to the spiro succinic anhydride with dehydration reagents like dicyclohexylcarbondiimide (DCC) or acetanhydride. It is treated in situ with xcfx89-aminoalkanoates to give the spiroimides. After removal of the protective group the reaction with 4-cyanobenzoyl chloride, formation of the amidine and saponification of the ester are carried out as described before. 
In a similar sequence 2-phenyl-1,3-dioxo-2,8-diaza-spiro[4.5]decanes are prepared. In contrast to Scheme 5A the intermediate succinic anhydride reacts with 4-aminobenzonitrile, and after deprotection of the spiropiperidine the intermediate is alkylated with xcfx89-halogenoalkanoates. The final steps of the synthesis are carried out in the usual manner. 
Scheme 6 illustrates the synthesis of 2-phenyl-1,3-dioxa-8-aza-spiro[4.5]decanes. N-protected 4-methylenepiperidine epoxides like benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate are hydrolyzed to 4-hydroxy-4-hydroxymethylpiperidines by heating with diluted aqueous hydrochloric acid (see Eur. Pat. Appl. EP 189 370). The spiro-bicycle is obtained by condensation of the diol with 4-cyanobenzaldehyd, which may be achieved by heating in toluene and catalytic amounts of 4-toluenesulfonic acid or by reaction in the presence of boron trifluoride. The following steps: removal of the protecting group, alkylation with xcfx89-halogenoalkanoates, formation of the amidine, and hydrolysis of the ester; are carried out as described in the previous Schemes. 
Scheme 7 describes the synthesis of 8-phenyl-1-oxa-3,8-diaza-spiro[4,5]decan-2-ones. 1-(4-Cyanophenyl)piperidin-4-ol is prepared by heating a mixture of 4-chlorobenzonitrile and piperidin-4-ol in DMF in the presence of sodium carbonate. The following oxidation to the piperidone is achieved with DMSO/oxalyl chloride (A. J. Mancuso, D. Swern, Synthesis 1981, 165), and the epoxide is formed by reaction with trimethylsulfoxonium iodide/sodium hydride in DMSO. After ring opening by reaction with xcfx89-aminoalkanoates the following steps of formation of the spiro derivative and the amidino acid are carried out according to methods described in Scheme 1. 
The synthesis of 1-oxa-4,9-diaza-spiro[5.5]undecan-3-ones is described in Scheme 8A (see R. D. Clark, J. M. Caroon, D. B. Repke, A. M. Strosberg, S. M. Bitter, M. D. Okada, A. D. Michel, R. L. Whiting, J. Med. Chem. 1983, 26, 855). N-protected 4-methylenepiperidine epoxides like benzyl 1-oxa-6-aza-spiro[2.5]octane-6-carboxylate are opened by heating with a methanolic solution of ammonia to give the corresponding 4-aminomethyl-4-hydroxypiperidine. The spiro-bicyclic nucleus is formed by the following condensation with chloroacetyl chloride. After removal of the benzyloxycarbonyl group with HBr in acetic acid the spiropiperidine is acylated with 4-cyanobe-nzoyl chloride. The subsequent steps of alkylation with xcfx89-halogenoalkanoates, formation of the amidine, and cleavage of the ester are carried out as described in the previous Schemes. 
Scheme 8B illustrates the synthesis of the related 1-oxa-4,9-diaza-spiro[5.5]undecanes. These are prepared by reduction of N(9)-protected 1oxa-4,9-diazo-spiro[5.5]undecan-3-ones with lithium aluminum hydride. After alkylation with xcfx89-halogenoalkanoates the protective group is removed, and the final steps of the sequence are carried out according to Scheme 8A. 
The synthesis of 1,3,8-triaza-spiro[4.5]dec-1-en-4-ones is described in Scheme 9 (see C. A. Bernhart, et al., J. Med. Chem. 1993, 2, 3371; C. del Campo, E. F. Llama, Org. Prep. Proced. Int. 1990, 2, 514). Protected 4-aminopiperidine-4-carboxamides are prepared by addition of potassium cyanide to corresponding piperidin-4-ones like N-benzylpiperidin-4-one followed by hydration of the nitrile intermediate. The spiro-bicyclic nucleus is obtained by heating with triethyl orthoformate or by reaction with gaseous formaldehyde. It is alkylated at the nitrogen in position 3 with xcfx89-halogenoalkanoates and the benzyl group is removed by hydrogenation. After acylation with 4-cyanobenzoyl chloride the amidinocarboxylic acid is prepared according to methods described in the previous Schemes. 
Scheme 10 describes the synthesis of (3-aza-spiro[5.5]undec-9-yl)acetic acid derivatives. After protection of ethyl isonipecotate with benzyl chloroformate the ester is reduced with lithiumaluminum hydride followed by Swern oxidation with oxalyl chloride/DMSO to corresponding 4-formylpiperidine. The spiro derivative is formed by condensation with 1-buten-3-one under basic conditions using potassium hydroxide, and the side chain is introduced by Hornerxe2x80x94Emmons reaction with diethyl (ethoxycarbonyl)methylphosphonate/sodium hydride. The bicyclic nucleus and the exocyclic double bond are saturated and the protective group is removed by catalytic hydrogenation with palladium hydroxide on charcoal. The subsequent acylation with 4-cyanobenzoyl chloride, formation of the amidine, and hydrolysis of the ethyl ester are carried out by methods described in the previous Schemes. 
Scheme 11a describes the preparation of 6,5 spiro-fused piperidino-carbamates in which the carbamate nitrogen is substituted with an acetic acid residue and the piperidine nitrogen is acylated with a benzamidine. In the first step, 4-piperidone (1) is allowed to react with TMSCN resulting in the formation of cyanohydrin (3). The nitrile moiety is reduced with LAH providing amino-alcohol (5), which is then allowed to react with diethyl carbonate in the presence of NaH ultimately forming spiro carbamate (7). Alkylation of the carbamate nitrogen is accomplished with NaH and alpha-bromo acetate giving ester (9). Catalytic hydrogenation removes the benzyl group providing free amine (11) which is acylated with 4-cyanobenzoic acid yielding (13). The nitrile moiety in (13) is converted to a protected amidine and is isolated as its Boc derivative. This material is then fully deprotected with TFA providing (15) as a salt. 
Materials containing a 6,6 spiro-fused piperidino-carbamate can be prepared in an analogous fashion (see Scheme 11b). Lithio-acetonitrile is allowed to react with 4-piperidone resulting in the formation of alcohol (17). This material can be transformed into final product (23) using the same set of reactions described for the conversion of (1) to (15). 
Scheme 11c describes the preparation of compounds containing a disubstituted 6,6 and 6,5 spirolactone. In the first step, piperidone 25 is allowed to react with the olefinic grignard reagent giving adduct 27. Oxidation of this material with permanganate affords lactone 29. Alkylation of the lactone enolate with an abromo ester provides the functionalized product 31. Removal of the Boc protecting group with TFA liberates amine 33 which can be acylated with 4-cyanobenzoic acid providing adduct 35. The nitrile moiety in this molecule can be converted to an amidine using the thio-Pinner protocol and then deprotected giving compound 39. 
Scheme 12 describes the preparation of 3,9-diazaspiro-[5.5]undecane compounds. The diazaspiro skeleton is prepared according to known procedures (see S. M. McElvain and R. E. Lyle, Jr., J. Am. Chem. Soc., 1967, 32, 1966). The intermediate diazasprirocyclic compound is alkylated by xcfx89-haloalkanoodes. After removal of the benzyl group, it is alkylated either by N-protected-4-(xcfx89-haloalkyl)piperidines or by corresponding pyridines, which are readily reduced to piperidines by hydrogenation as shown in the experimental section below. In a similer manner, any other basic residue with an appropriate spaced is prepared. 
1-Monoesters of aspartic acid (n=1) or glutamic acid (n=2), N-protected derivatives of these monoesters, or other similarly protected compounds are commercially available or have been described previously in the literature. See Gregory et al., J. Chem. Soc. (c), 1968, 715; Olsen et al., J. Org. Chem., 1984, 49, 3527; Yang and Menifield, J. Org. Chem., 1976, 41, 1032; Taschner et al., Liebigs Ann. Chem., 1961, 646, 123, 125, 127, 134. These compounds are connected to sulfonamides by reaction with sulfonyl chlorides. Preferred sulfonyl chlorides are benzenesulfonyl chloride or n-butanesulfonyl chloride. The 3,9-diazaspiro-[5.5]undecane compound from Scheme 12 is acylated by these intermediates, followed by removal of the portective group. It is acylated by N-protected xcfx89-aminocarboxylic acids bearing protective groups, such as t-butoxycarbonyl or benzyloxycarbonyl. The protective group is removed and the free amine is converted to a guanidine, which is optionally protected using standard procedures such as by reaction with N,Nxe2x80x2-bis(t-butoxycarbonyl)thiourea and heavy metal salts (e.g. copper or mercury). 
Scheme 14 outlines the preparation of the 6,5 (n=1) and 6,6 (n=2) spiro-carbamates with substitution of a basic residue on the piperidine nitrogen and an acidic residue on the carbamate nitrogen. The protected compound is deprotonated with sodium hydride in an aprotic solvent, such tetrahydrofuran, and the resulting sodium salt is reacted with an xcex1-halo ester to provide the mono-substituted products. These compounds are then deprotected to give the secondary amines. These materials are then acylated giving N-alkylated, N-acylated intermediate products. The nitrile group is transformed to an amidino group using a modified thio-Pinner sequence. More specifically, reaction of the nitrile to form the thioamide followed by S-alkylation with methyl iodide, and then displacement with ammonia. Preferably, the intermediate compounds are not isolated but are reacted with di-t-butyl dicarbonate to give the protected amidines. These intermediate compounds are fully deprotected, for example with trifluoroacetic acid, to give the desired products. 
Scheme 15 outlines the preparation of 6,5 spiro-carbamates with substitution of an alkyl guanidine on the piperidine nitrogen, and an acicic residue on the carbamate nitrogen. The intermediate compound prepared as described in Scheme 14, is acylated with protected amino acids providing the intermediate amide compounds. The protecting groups are then removed using reactions well known in the chemical arts, and materials are guanylated providing the fully-protected intermediate compounds. Complete deprotection, for example with trifluorocacetic acid, provides the desired compounds. 
Scheme 16 describes the synthesis of spiro-carbamates containing an oxygen-linked basic group, where n is 1 or 2. The starting compound is alkylated on nitrogen by reacting with a strong base, such as sodium hydride, and an alkylating agent, such as an xcex1-bromo-t-butyl acetate. The protecting group for the ketone functional group is then removed, and the ketone reduced with a hydride reducing agent, such as sodium borohydride, to provide a mixture of alcohols. The alcohols are alkylated with 4-cyanobenzyl bromide, and the resulting compound is transformed into the protected amidine. 
Scheme 17 describes the synthesis of spiro carbamates containing an amide-linked basic group on the saturated ring. The intermediate ketone, prepared as shown in Scheme 16, is reductively aminated with an amine and sodium cyanoborohydride. This intermediate compound is acylated with 4-cyanobenzoic acid providing the amide intermediate. This amide is converted to the protected amidine using procedures well known in the chemical arts. The resulting compound is converted into the desired compound using procedures as described previously. 
The Scheme 37 describes the synthesis of (8-benzoyl-aza-spiro[5.4]dec-3-yl)acetic acid derivatives. The reaction of N-benzyl-piperidone with diethyl lithiopyrrolidinomethyl phosphonate will give enamine. The enamine can be directly alkylated with 2-bromo-3-iodopropene, followed by aqueous hydrolysis to give the alkylated aldehyde. The hydrolysis of vinyl bromide can be readily achieved with mercuric acetate and boron trifluoride etherate in glacial acetic acid at room temperature (see S. F. Martin, and T. Chou, J. Org. Chem. 1978, 43, 1027). The xcex3-keto aldehyde will be treated with aqueous potassium hydroxide in methanol to afford cycloaldolization and dehydration to give the key intermediate spiro[4.5]dienone. The side chain is introduced by Horner-Emmons reaction with triethylphosphono acetate or triethyl phoshono propionate/sodium hydride. The bicyclic nucleus and the exo cyclic double bond are saturated and the protective group is removed by catalytic hydrogenation with palladium hydroxide on carbon. The subsequent acylation with 4-cyanobenzoyl chloride or (2-fluoro-4-cyanobenzoyl chloride), formation of amidine, and hydrolysis of the ester are carried out by methods described in the previous Schemes. 
The Scheme 38 describes the synthesis 8-benzoyl-1-3-acyl-spiro[4.5]dec-1-en. The mono protected spiro-imidazoline from Scheme 33 is acylated with appropriate ester-acid chloride. The protecting group is removed followed with acylation with 4-cyanobenzoyl chloride (or 2-fluoro-4-cyanobenzoyl chloride) in presence of base such as triethylamine. After ester hyrolysis, the nitrile is converted to amidine funtionality as described in earlier schemes. 
Scheme 40 describes the synthsis of a lactam. The imide was reduced with LiAlH4 in THF to afford the amine. It was then N-debenzylated under hydrogenolysis conditions. The free piperidino compound was reacted with carboxy group bearing compounds as described before. De-protection of the carboxy groups followed by conversion of the cyano to amidino yielded the desired compounds. 
Scheme 41 1-Benzylpiperidone was condensed with 4-methoxybenzylamine followed by reaction with potassium cyanide. The cyano group was hydrolysed by reaction with hot conc. HCl. Then it was coupled with 4-carboxyamido aniline to afford the amide. The 4-methoxy benzyl protective group was removed by reaction with DDQ, followed by reaction of the free amine with carbonyl diimidazole to give rise to urea derivative. N-De-benzylation was achieved under hydrogenolysis conditions, followed by coupling with carboxy group bearing synthons. 
Scheme 42 1-Benzylpiperidone was condensed with ethyl cyanoacetate and ammonia in ethanol as described in the literature {S. M. McElvain, R. E. Lyle, Jr.; J. Amer. Chem. Soc. 72, 384 (1950)}. This was then treated with conc. Hcl at reflux for 3 days to afford the diacid, which was purified by its conversion to diethylester followed by hydrolysis back to diacid. This was then converted to the anhydride, and treated with 4-carboxyamido aniline as described in scheme 1 to afford the imide. This imide was converted to lactam by reaction with NaBH4 as described in Scheme 39. The rest of the sequence was carried out as described elsewhere in the application. 
Scheme 43 1-Benzylpiperidone was coupled with 4-carboxyamide aniline, and the imide was reacted with potassium cyanide. This amine nitrile was reacted with potassium cyanate under acidic conditions to yield the hydantoin. The hydantoin functionality was reduced to urea by reaction with NaBH4, as described before. 
Scheme 44 1-Benzylpiperidone was coupled with 4-methoxy benzylamine, and the imine was then reacted with 4-carboxamide aniline to yield the amine nitrile. The 4-methoxy benzyl group was deprotected by reaction with DDQ. The free amine thus obtained was treated with potassium cyanate under acidic conditions to afford the hydantoin. The rest of the sequence is described elsewhere in the patent. 
Scheme 45 1-Benzylpiperidone was coupled with ethyl cyanoacetate to afford the addition product, which was then reaacted with potassium cyanide in ethanol/water at reflux to yield the dinitrile. It was reduced with LiAlH4 to afford the diamine. It was then reacted with carbonyl diimidazole to yield the 7-membered urea. This was subjected to N-debenzylation followed by coupling of the free piperidino compound with 4-cyano phenyl triflate under palladium catalysis. The rest of the sequence is described elsewhere. 
Scheme 46 4-carboxamide aniline was reacted with the epoxide (synthesis of it is described elsewhere in this application) to afford the aminol. The hydroxy group was protected as tert-butyl dimethylsilyl ether, and the amine was then reacted with chloro acetyl chloride. Then the TBS protective group was removed and the free hydroxy compound was cyclized to yield the spiro compound. the rest of the steps are identical to procedures described in other schemes
The following Examples illustrate the practice of the invention.